Deposition of beta-amyloid (Abeta) in vulnerable brain regions is an invariable feature of Alzheimer's disease (AD). Abeta is formed by the regulated cleavage of the amyloid precursor protein (betaAPP). The metabolism of betaAPP has been elucidated mainly by studies in clonal cell lines transfected with human betaAPP. However, since neurons are the most abundant source of Abeta and are the most affected cell-type in AD, the study of betaAPP metabolism and Abeta generation in neurons will be important to elucidate the biological processes occuring in the brain of those afflicted by AD. Our objective is to study the endogenous processing and intracellular trafficking of Abeta and betaAPP in rodent primary neuronal cultures. Furthermore, we are investigating whether the relative utilization of processing pathways for betaAPP are regulated in a similar manner in neuronal cultures as has been observed in cell lines. Known regulators of betaAPP metabolism, such as protein phosphorylation and first messenger neurotransmitter signal transduction systems, and gonadal hormone treatment are being assessed in these cortical cultures. Using radiosequencing and metabolic labeling- mass spectrometry, we have recently discovered that variant AbetaGlu11 peptides are principal Abeta species secreted by neurons. Moreover, we have found that treatment of neurons with 17beta-estradiol or protein phosphatase inhibitors are especially effective at reducing secretion of amyloidogenic Abeta peptides. The elucidation of the molecular and cellular processes governing the metabolism of betaAPP and Abeta in neurons will provide important information in the pursuit of rational therapeutic strategies for AD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS002037-02
Application #
6187469
Study Section
NST-2 Subcommittee (NST)
Program Officer
Heemskerk, Jill E
Project Start
1999-04-01
Project End
2002-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
2
Fiscal Year
2000
Total Cost
$116,829
Indirect Cost
Name
Rockefeller University
Department
Other Basic Sciences
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
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